Biomedical subjects

Y Michotte

Publications and source records attributed to Y Michotte.

At least 19 recordsLinked to original sources

PubMed2004

Postischemic mild hypothermia reduces neurotransmitter release and astroglial cell proliferation during reperfusion after asphyxial cardiac arrest in rats.

The present study investigated whether postischemic mild hypothermia attenuates the ischemia-induced striatal glutamate (GLU) and dopamine (DA) release, as well as astroglial cell proliferation in the brain. Anesthetized rats were exposed to 8 min of asphyxiation, including 5 min of cardiac arrest. The cardiac arrest was reversed to restoration of spontaneous circulation (ROSC), by brief external heart massage and ventilation within a period of 2 min. After the insult and during reperfusion, the extracellular glutamate and dopamine overflow increased to, respectively, 3000% and 5000% compared with the baseline values in the normothermic group and resulted in brain damage, ischemic neurons and gliosis. However, when hypothermia was induced for a period of 60 min after the insult and restoration of spontaneous circulation, the glutamate and dopamine overflows were not significantly different from that in the sham group. Histological analysis of the brain showed that postischemic mild hypothermia reduced brain damage, ischemic neurons, as well as astroglial cell proliferation. Thus, postischemic mild hypothermia reduces the excitotoxic process, brain damage, as well as astroglial cell proliferation during reperfusion. Moreover, these results emphasize the trigger effect of dopamine on the excitotoxic pathway.

Animals↗

PubMed2004

Formalin-induced spinal glutamate release in freely moving rats: comparison of two spinal microdialysis approaches.

Two different spinal microdialysis approaches using either a linear tissue probe (LM-3) or a loop probe were explored on freely-moving rats to investigate the basal and formalin-evoked release of glutamate (Glu) in the spinal dorsal horn or in the cerebrospinal fluid (CSF). Adult male Wistar rats were implanted either with a LM-3 probe transversely through the spinal dorsal horn or with a loop probe in the CSF. After 24 hours recovery, microdialysis was initiated with perfusion of modified Ringer's solution at a flow rate of 5 microliters/min and the basal Glu concentrations were sampled for 1 hour. The effects of altering the microdialysis flow rate and perfusion solution on basal Glu release were next investigated. Following the injection of 50 microliters of formalin 5% into the hind paw, 10-min samples were collected for 90 min. The baseline levels of Glu were 0.82 +/- 0.09 microM with LM-3 probes and 5.96 +/- 0.22 microM with the loop probes. Decreasing the flow rate from 5 to 2 microliters/min increased extracellular Glu concentrations by 222.7 +/- 7.3%, whereas perfusion with artificial CSF reduced baseline Glu by 61.5 +/- 9.5% with LM-3 probes. Injection of formalin induced a short-lasting but significant increase of Glu with a similar profile and time course when using either of the microdialysis approaches. In conclusion, microdialysis in the dorsal horn or in the CSF are both effective techniques to assess the alterations in Glu release following peripheral nociceptive input. The loop probe technique in CSF is more reproducible for routine investigation of drug effects, whereas the microdialysis of the dorsal horn provides a useful tool to precisely locate where the release of the neurotransmitters occurs.

Analysis of Variance↗

PubMed2003

Effects of venlafaxine on extracellular 5-HT, dopamine and noradrenaline in the hippocampus and on peripheral hormone concentrations in the rat in vivo.

The purpose of the present study was to study the effect of an acute dose of the serotonin (5-HT) - noradrenaline (NA) reuptake inhibitor venlafaxine on extracellular concentrations of 5-HT, NA and dopamine (DA) in the hippocampus and on the peripheral hormone concentrations in freely moving rats. Blood obtained from a catheter placed in the vena femoralis was analyzed for adrenocorticotropin (ACTH), beta-endorphins, prolactin (PRL), growth hormone (GH) and cortisol. Collections are referred to pre and post injection of 20 mg/kg of venlafaxine. Extracellular hippocampal NA and 5-HT as determined with in vivo microdialysis increased significantly after drug injection. PRL and ACTH were significantly affected by the drug. At the selected dose venlafaxine is able to increase the release of 5-HT but also of NA in rat hippocampus. Due to the dual reuptake properties of the drug and the functional interconnection of the NA and the 5-HT systems, the observed effects on peripheral hormones are possibly mediated by a combined action of these 2 systems.

Adrenergic Uptake Inhibitors↗

PubMed2003

Effect of bupropion on hippocampal neurotransmitters and on peripheral hormonal concentrations in the rat.

The purpose of the present study was to administer an acute dose of the dual dopamine norepinephrine reuptake blocker bupropion in freely moving rats and to monitor the extracellular neurotransmitter concentrations in the hippocampus via in vivo microdialysis and the peripheral hormonal concentrations via catheterization. A microdialysis probe was inserted in the hippocampus, and samples for serotonin, dopamine, and norepinephrine were collected every 20 min before and after the injection of 17 mg/kg of bupropion, for a total sampling time of 180 min. A catheter was placed in the vena femoralis of the second group of rats, and blood samples were collected before and after bupropion injection for quantification of growth hormone, prolactin, corticosterone, adrenocorticotropin hormone, and beta-endorphins. All neurotransmitter levels (dopamine, norepinephrine, and serotonin) significantly increased after bupropion injection. This was accompanied by a significant decrease in prolactin concentrations, whereas the other hormones showed no statistically significant variation. It can, therefore, be concluded that, although bupropion has dual reuptake proprieties, the observed effects both at the central and at the peripheral level seem to be ruled by the dopaminergic system.

Animals↗

PubMed2002

Convulsant and subconvulsant doses of norfloxacin in the presence and absence of biphenylacetic acid alter extracellular hippocampal glutamate but not gamma-aminobutyric acid levels in conscious rats.

Fluoroquinolones are antibiotics with central excitatory side effects. These adverse effects presumably result from inhibition of gamma-aminobutyric acid (GABA) binding to GABA(A) receptors. This GABA antagonistic effect is greatly potentiated by the active metabolite of fenbufen, biphenylacetic acid (BPAA). Nevertheless, it remains questionable whether GABA receptor antagonism alone can explain the convulsant activity potentials of these antimicrobial agents. The present study was undertaken to investigate the possible effects of norfloxacin, both in the absence and in the presence of BPAA, on the extracellular hippocampal levels of GABA and glutamate, the main central inhibitory and excitatory amino acid neurotransmitters, respectively. This in vivo microdialysis approach with conscious rats allows monitoring of behavioral alterations and concomitant transmitter modulation in the hippocampus. Peroral administration of 100 mg of BPAA per kg of body weight had no effect on behavior and did not significantly alter extracellular GABA or glutamate concentrations. Intravenous perfusion of 300 mg of norfloxacin per kg did not change the rat's behavior or the concomitant neurotransmitter levels in about half of the experiments, while the remaining animals exhibited severe seizures. These norfloxacin-induced convulsions did not affect extracellular hippocampal GABA levels but were accompanied by enhanced glutamate concentrations. Half of the rats receiving both 100 mg of BPAA per kg and 50 mg of norfloxacin per kg displayed lethal seizures, while the remaining animals showed no seizure-related behavior. In the latter subgroup, again no significant alterations in extracellular GABA levels were observed, but glutamate overflow remained significantly elevated for at least 3 h. In conclusion, norfloxacin exerts convulsant activity in rats, accompanied by elevations of extracellular hippocampal glutamate levels but not GABA levels, even in the presence of BPAA.

Administration, Oral↗

PubMed2001

The effects of LY393613, nimodipine and verapamil, in focal cerebral ischaemia.

This study evaluates the effects of N-(2-[bis (4-fluorophenyl)methoxy]ethyl)-1-butanamine hydrochloride (LY393613), a novel neuronal (N/P/Q-type) Ca(2+) channel blocker, in ischaemia. For comparison, two commonly used L-type Ca(2+) channel blockers; nimodipine and verapamil were also evaluated. Ischaemia was induced in freely moving rats by micro-injection of endothelin-1 near the middle cerebral artery. In vivo microdialysis, laser Doppler flowmetry and histology were used to monitor ischaemia. Administration of LY393613, before and after the insult, attenuated the ischaemia-induced glutamate release, but not the dopamine release. Both nimodipine and verapamil failed to affect transmitter releases significantly, when administered post-occlusion. None of the compounds tested, produced any significant change in striatal blood flow. Histology showed that ischaemic damage was significantly less in LY393613 pre-treated rats. In conclusion, LY393613, a neuronal N/P/Q-Ca(2+) channel blocker, can attenuate ischaemic brain damage. The protective mechanism appears to be mainly the attenuation of the ischaemia-induced glutamate release, rather than its effect on cerebral hemodynamics.

Amines↗

PubMed2001

Benserazide decreases central AADC activity, extracellular dopamine levels and levodopa decarboxylation in striatum of the rat.

In Parkinsonian patients treated with levodopa, peripheral decarboxylase inhibitors like carbidopa and benserazide are used to increase the central availability of levodopa. In experimental animal studies, this clinical situation is mimicked. However, at the dose used in many animal studies, both benserazide and carbidopa pass the blood brain barrier. In this study, we investigated to what extent their presence in brain inhibits striatal aromatic amino acid decarboxylase activity. At 50 mg/kg i.p., both carbidopa and benserazide decreased striatal decarboxylase activity. At 10 mg/kg i.p., only benserazide decreased the enzyme activity, but this did not change extracellular dopamine in striatum and allowed dopamine levels to increase after levodopa administration. In contrast, the inhibition of central decarboxylase activity by 50 mg/kg benserazide decreased striatal dopamine levels and prevented the levodopa-induced increase. Therefore, it is important to carefully consider the dose of the peripheral decarboxylase inhibitor used when the central effects of levodopa are studied.

Animals↗

PubMed2001

2-chloro-N(6)-cyclopentyladenosine-elicited attenuation of evoked glutamate release is not sufficient to give complete protection against pilocarpine-induced seizures in rats.

The effects of 2-chloro-N(6)-cyclopentyladenosine (CCPA) perfused intrahippocampally (1 microM) and injected intraperitoneally (0.5 mg/kg) were investigated in focally-evoked pilocarpine-induced (10 mM) seizures in freely moving rats. While the intrahippocampal perfusion of this highly selective adenosine A(1) receptor agonist gave complete protection against pilocarpine-induced seizures, systemic administration only partially protected the animals, as evaluated by concomitant behavioural and electrocorticographical (ECoG) observations and monitoring of the neurotransmitter alterations. However, pilocarpine-evoked elevation of hippocampal glutamate overflow was significantly attenuated by CCPA irrespective of the mode of administration. Acute pretreatment with systemic 8-cyclopentyl-1,3-dipropylxanthine, a selective A(1) antagonist, reversed both the partial protective effect and the attenuating effect on the extracellular glutamate elicited by systemic CCPA administration. Intrahippocampal CCPA markedly reduced basal hippocampal dopamine efflux but not GABA or glutamate and considerably attenuated the pilocarpine-evoked elevation in dopamine levels. Systemic CCPA appeared to have little influence on the overall pattern of dopamine elevation. The findings give evidence that CCPA-elicited abatement of the evoked glutamate release alone, cannot fully account for its anticonvulsant effect and may suggest that the effects mediated by adenosine on postsynaptic adenosine receptors could be more crucial for its anticonvulsant effect.

Adenosine↗

PubMed2001

Mild hypothermia induced by a helmet device: a clinical feasibility study.

STUDY OBJECTIVE: To test the feasibility and the speed of a helmet device to achieve the target temperature of 34 degrees C in unconscious after out of hospital cardiac arrest (CA). METHODS: Patients with cardiac arrest due to asystole or pulseless electrical activity (PEA) who remained unconscious after restoration of spontaneous circulation (ROSC) were enrolled in the study and randomised into two groups: a normothermic group (NG) and a hypothermic group (HG). Bladder and tympanic temperature were monitored every 15 min. A helmet device was used to induce mild hypothermia in the HG. Later on, the effect of mild hypothermia on the haemodynamics, electrolytes, lactate, arterial pH, CaO2, CvO2 and O2 extraction ratio were analysed and compared to the values obtained from the NG. RESULTS: Thirty patients were eligible for the study, 16 were randomised into the HG and 14 were randomised into the NG. The median tympanic temperature at admission in both groups was 35.5 degrees C (range: 33.3-38.5 degrees C) and the median tympanic temperature after haemodynamic stabilisation was 35.7 degrees C (range: 33.6-38.2 degrees C). In the HG, the core and the central target temperature of 34 degrees C were achieved after a median time of 180 and 60 min, respectively after ROSC. At the start of the study, no significant differences between the NG and HG were seen. At the end of the study, lactate concentration and O2 extraction ratio were significantly lower in the HG; however the CvO2 was significantly lower in the NG. CONCLUSIONS: Mild hypothermia induced by a helmet device was feasible, easy to perform, inexpensive and effective, with no increase in complications.

Body Temperature↗

PubMed2001

Effects of dietary sucrose on hippocampal serotonin release: a microdialysis study in the freely-moving rat.

The effects of dietary supplementation with either sucrose or starch (50 g/kg regular food for 2 weeks) on central 5-hydroxytryptamine (5HT; serotonin) release were investigated in freely-moving rats. It has been suggested that the amount of transmitter that serotoninergic neurons release might be altered by food intake. We monitored the effects of sucrose and starch on concentrations of extracellular 5HT, its metabolite 5-hydroxyindoleacetic acid (5HIAA), gamma-aminobutyric acid (GABA) and dopamine in the hippocampus, using in vivo microdialysis. The major finding was that baseline levels of extracellular hippocampal 5HT in rats with ad libitum access to food supplemented with sucrose were significantly higher compared with the starch control group. We then verified that sucrose supplementation affected the potency of S(+)fenfluramine to increase hippocampal 5HT levels. In both groups of rats, acute intraperitoneal injection (1 mg/kg) of this anorectic drug induced a response curve of the extracellular hippocampal 5HT levels, with a shape that corresponded with earlier data for different brain areas often using up to 10-fold higher doses of S(+)fenfluramine. Nevertheless, we showed that throughout the experiment the absolute values of the sucrose response curve remained higher than in the starch group. On the other hand, S(+)fenfluramine exerted longer lasting effects in the starch group, as compared with the sucrose group. Significant decreases in levels of extracellular hippocampal 5HIAA levels following S(+)fenfluramine administration were simultaneously observed. A practical implication of the present findings is that dietary sucrose may bias the results of studies investigating brain serotoninergic mechanisms and the effects of (anorectic) drugs interacting with 5HT systems in the hippocampus.

Animals↗

PubMed2000

Neurochemical changes and laser Doppler flowmetry in the endothelin-1 rat model for focal cerebral ischemia.

Generalized neurotransmitter overflow into the extracellular space, after cerebral ischemia, has been suggested to contribute to subsequent neuronal death. This study aims to investigate the striatal release of the neurotransmitters dopamine (DA), glutamate (Glu) and gamma-aminobutyric acid (GABA) by means of microdialysis, in a rat model for focal transient cerebral ischemia. Ischemia was induced by the application of 120 pmol endothelin-1 (Et-1), adjacent to the middle cerebral artery (MCA) in freely moving rats. Ischemia produced a large increase in extracellular striatal DA concentrations (2400%), Glu (5500%) and GABA (800%) concentrations. Laser Doppler flowmetry in anaesthetized rats, indicated that the blood flow within the striatum decreased by 75+/-11%. The period of sustained drop of blood flow, was dose-dependently related to the concentration Et-1 injected. Histological analysis of brain slices, taken from anaesthetized and conscious animals, indicated a 500 pmol dose of Et-1 was required to produce a similar infarct in anaesthetized rats to a 120 pmol dose of Et-1 in freely moving rats. The immediate drop in striatal blood flow, and the prompt increase of extracellular DA, after the micro-application of Et-1, were quite striking. This suggests that the DA release, rather than the Glu overflow may be the primary event initiating the cascade of processes ultimately leading to cell death and neurological deficits.

Animals↗

PubMed2000

MK801 influences L-DOPA-induced dopamine release in intact and hemi-parkinson rats.

In vivo microdialysis was used to investigate the influence of dizocilpine (MK801) on basal and levodopa (L-DOPA)-induced extracellular dopamine levels in striatum and substantia nigra of intact and 6-hydroxydopamine-lesioned rats. In lesioned rats, extracellular dopamine was decreased in striatum but not in substantia nigra. L-DOPA (25 mg/kg i.p. after benserazide 10 mg/kg i. p.) increased the dopamine levels in striatum and substantia nigra of intact and dopamine-depleted rats. This increase was significantly higher in dopamine-depleted compared to intact striatum. Pretreatment with MK801 (0.1 and 1.0 mg/kg i.p.) dose-dependently attenuated the L-DOPA-induced dopamine release in substantia nigra of intact rats. In dopamine-depleted striatum, MK801 enhanced L-DOPA-induced dopamine release. The present results indicate that the influence of MK801 on L-DOPA-induced dopamine release in striatum and substantia nigra depends on the integrity of the nigrostriatal pathway. In Parkinson's disease, NMDA receptor antagonists could be beneficial by enhancing the therapeutic efficacy of L-DOPA at the level of the striatum.

Adrenergic Agents↗

PubMed2000

Flumazenil prevents diazepam-elicited anticonvulsant action and concomitant attenuation of glutamate overflow.

Systemic administration of diazepam (5 mg/kg, i.p.) produced a prompt anticonvulsant effect in pilocarpine-induced seizures in freely moving rats. The anticonvulsant effect was associated with significant attenuation of pilocarpine-evoked increases in extracellular hippocampal glutamate levels to below the baseline levels. The purpose of the present microdialysis study, therefore, was to investigate if the effect of diazepam on glutamate release was mediated at the level of the benzodiazepine gamma-aminobutyric acid(A) (GABA(A)) receptor complex to preclude any non-GABAergic mechanisms. Systemic administration of the specific benzodiazepine-receptor antagonist flumazenil (10 mg/kg, i.p. )-elicited complete reversal of diazepam-evoked anticonvulsant action and concomitant attenuation of extracellular glutamate efflux below the baseline levels. This provides evidence that under the given experimental conditions, diazepam-evoked alterations in glutamate overflow associated with the anticonvulsant action were indeed mediated at the level of benzodiazepine-GABA(A) receptor complex, possibly involving the modulation of both pre- and post-synaptic sites of the receptor complex.

Animals↗

PubMed2000

LY377770, a novel iGlu5 kainate receptor antagonist with neuroprotective effects in global and focal cerebral ischaemia.

We have evaluated the neuroprotective effects of the decahydroisoquinoline LY377770, a novel iGlu5 kainate receptor antagonist, in two models of cerebral ischaemia. Global ischaemia, induced in gerbils by bilateral carotid artery occlusion (BCAO) for 5 min, produced a large increase in locomotor activity at 96 hr post-occlusion and a severe loss of CA1 cells in the hippocampus histologically at 120 hr post-occlusion. LY377770 (80 mg/kg i.p. 30 min before or 30 min after BCAO followed by 40 mg/kg i.p. administered at 3 and 6 hr after the initial dose) attenuated the ischaemia-induced hyperactivity and provided (92%) and (29%) protection in the CA1 cells respectively. This protection was greater than that seen with maximally tolerated doses of other glutamate receptor antagonists (CGS19755, CPP, MK-801, ifenprodil, eliprodil, HA-966, ACEA1021, L701,324, NBQX, LY293558, GYKI52466 and LY300164). Focal ischaemia was induced by infusing 200 pmol of endothelin-1 (Et-1) adjacent to the middle cerebral artery and LY377770 was administered at 80 mg/kg i.p. immediately, 1 or 2 hr post-occlusion followed by 40 mg/kg i.p. 3 and 6 hr after the first dose. The infarct volume, measured 72 hr later, was reduced by LY377770 when given immediately (P<0.01), at 1 hr (P<0.05) but not significantly at 2 hr post-occlusion. Reference compounds, LY293558 (20 mg/kg i.p. and then 10 mg/kg as above) and MK-801 (2.5 mg/kg i.p. ), both administered immediately post-occlusion produced significant (P<0.05) but somewhat less neuroprotection. In parallel microdialysis studies, LY377770 (75 mg/kg i.p.) attenuated ischaemia-induced increases in extracellular levels of glutamate, but not of dopamine. In conclusion, these results indicated that iGlu5 kainate receptors play a central role in ischaemic brain damage following global and focal cerebral ischaemia. LY377770 is a novel, soluble, systemically active iGlu5 antagonist with efficacy in global and focal ischaemia, even when administered post-occlusion. LY377770 may therefore be useful as a neuroprotectant in man.

Animals↗

PubMed2000

Muscarinic antagonists in substantia nigra influence the decarboxylation of L-dopa in striatum.

This study was designed to investigate whether anticholinergic drugs acting at the level of the substantia nigra can affect basal extracellular dopamine concentrations and the levodopa (L-dopa)-induced increases in dopamine levels in the striatum. Dual probe in vivo microdialysis in freely moving rats was used. One microdialysis probe was implanted in the substantia nigra and the other in the ipsilateral striatum. Muscarinic receptor antagonists were perfused into the substantia nigra and changes in neurotransmitter levels in the substantia nigra and at the axon terminals in the striatum were monitored simultaneously. Nigral perfusion of the non-selective muscarinic receptor antagonist trihexyphenidyl (1 mM) produced an increase in extracellular dopamine and gamma-aminobutyric acid (GABA) levels in the substantia nigra. Perfusion with the muscarinic M(1) receptor antagonist telenzepine (0.1 microM) produced a significant decrease in nigral dopamine and GABA levels in the substantia nigra. The muscarinic M(2) receptor antagonist methoctramine (75 microM) produced an increase in dopamine levels in the substantia nigra. No significant changes in nigral extracellular GABA levels were observed. The L-dopa-induced increases in extracellular dopamine levels in the striatum were clearly attenuated under nigral perfusion of these drugs. This in vivo study demonstrates that anticholinergic drugs perfused at the level of the substantia nigra can modulate dopamine and GABA levels and attenuate the L-dopa decarboxylation in the striatum, possibly via modulation of the nigrostriatal dopaminergic system. We add further evidence that the substantia nigra is an important site of action of antimuscarinic drugs. The attenuation of L-dopa-induced dopamine release in the striatum exerted by nigral perfusion of these antimuscarinic drugs is probably mediated via different mechanisms. This attenuation is regarded as a beneficial effect of the muscarinic antagonists as adjuncts to L-dopa in Parkinson's disease treatment. We postulate that drugs that enhance dopamine release, after L-dopa administration, in a less extreme way than L-dopa administered on its own could prevent further neurodegeneration and dyskinesias thought to result from extremely high extracellular dopamine levels following L-dopa treatment.

Analysis of Variance↗

PubMed2000

Neostigmine influences the L-dopa-induced extracellular dopamine levels in the striatum.

Using in vivo microdialysis in freely moving rats, we show that the addition to the dialysis perfusion fluid of the acetylcholinesterase inhibitor neostigmine influences the decarboxylation of levodopa (L-dopa). Continuous perfusion of neostigmine (10, 50 and 100 nM) in striatum attenuated the L-dopa-induced dopamine release in a dose-dependent manner. This effect suggests that changes in magnitude of drug responses may occur when an acetylcholinesterase inhibitor is included in the perfusion solution. Results obtained under these circumstances should be carefully interpreted concerning the pharmacological effects of other drugs when used concomitantly with neostigmine.

Animals↗

PubMed2000

Development and evaluation of a linear regression method for the prediction of maximal chiral separation of basic drug racemates by cyclodextrin-mediated capillary zone electrophoresis.

An important step in method development of chiral separations with neutral cyclodextrins (CDs) as chiral selectors is the estimation of the CD concentration that gives the highest degree of separation. From the equation [S]opt=1/(K1K2)(1/2) this optimal CD concentration can be calculated if any knowledge is available about the binding constants K1 and K2 of both enantiomer complexes. These values can be obtained by measuring the effective velocities of each enantiomer as a function of the selector concentration and fitting these profiles by non-linear least-square regression. An alternative approach has been developed which makes it possible to predict the optimal CD concentration from a few experiments performed at low CD concentrations. The model is developed using some antimycotic imidazole derivatives (econazole, miconazole and isoconazole) as test substances and hydroxypropyl-beta-CD as chiral selector. The results obtained by this method are in good agreement with those from non-linear least-square regression.

Cyclodextrins↗

PubMed2000

Anticonvulsant effect and neurotransmitter modulation of focal and systemic 2-chloroadenosine against the development of pilocarpine-induced seizures.

The present microdialysis study was aimed at evaluating the anticonvulsant effect of the adenosine A(1) receptor agonist 2-chloroadenosine (2-CADO) against pilocarpine-induced seizures in rats. The hippocampal neurotransmitter modulation on the action of 2-CADO and its possible activation of hippocampal adenosine A(2a) receptors was also assessed. Intrahippocampal perfusion of 2-CADO (100 microM) produced a sustained attenuation of baseline dopamine levels, while eliciting a delayed augmentation of both glutamate and GABA efflux. When co-perfused with pilocarpine (10 mM) or injected systemically (7.5 mg/kg), 2-CADO prevented the development of seizures as well as pilocarpine-evoked augmentation of the glutamate and dopamine levels. However, the delayed increase in glutamate overflow with intrahippocampal 2-CADO was still observed. Intraperitoneal injection of selective adenosine A(2a) receptor antagonist SCH 58261 reversed the 2-CADO-elicited attenuation of pilocarpine-induced increment in dopamine efflux and completely abolished the delayed augmentation of glutamate levels, irrespective of perfusion with pilocarpine. Intraperitoneal injection of 5 mg/kg 2-CADO mostly prevented the elevation of pilocarpine-induced glutamate efflux but could not confer adequate protection. We conclude that 2-CADO can prevent pilocarpine-induced seizures by both intrahippocampal perfusion and systemic administration. The attenuation of pilocarpine-induced dopamine efflux and the late elevations of glutamate are likely to be mediated by hippocampal A(2a) receptors. Inhibition of presynaptic glutamate release does not appear to be sufficient for the anticonvulsant action. Postsynaptic events could play a more important role.

2-Chloroadenosine↗